Scientific Evaluation of Medicinal Plants Used for the Treatment of Cervicitis (Qorohe- Rahem) in Iranian Traditional Medicine

Cervicitis is an inflammatory condition of the cervix associated with upper genital tract infection and reproductive complications. Treatment for cervicitis in conventional system is the use of antibiotics and antifungal therapies and surgical interventions, but none of these treatments provides the definite efficacy in spite of high cost and side effect. So there is a need for an alternate therapy which is safe, effective, easily available and free from side effects. This review focuses on medicinal plants mentioned in main Iranian Traditional Medicine reference books. Medicinal plants mentioned in Iranian Traditional Medicine for treatment of Cervicitis were elicited and searched in electronic databases including Pub Med, Scopus, Science direct and Google Scholar to find studies that confirmed their efficacy. The findings included 31 plants belonging to 21 families. Research findings showed that the plants mentioned in Iranian Traditional Medicine resources can contribute to the recovery and treatment of cervicitis through anti- inflammatory, antioxidant, antibacterial and anti- fungal, wound healing and analgesic effects. Finding the medicinal plants effective on cervicitis based on ITM could suggest a better strategy for relieving and management of cervicitis symptoms especially in recurrent or persistent condition.


Introduction
Cervicitis is a syndrome of cervical inflammation (1, 2) which is clinically defined as the presence of either mucopurulent discharge or cervical friability (easily bleeding induced by gentle passage of a swab through the Endocervical os) (1-6). More subtle signs of cervicitis include edema of the cervical ectropion (edematous ectopy) and vaginal pain (1,3,4,6). Sacral backache, lower abdominal pain, and dyspareunia are other symptoms of cervicitis (4). Microscopic definitions involving the use of gram stain of cervical secretions includes either more than 10 white blood cells (WBCs) or more than 30 WBCs per high-power field (1,3,4,6). Also, there is an evidence that it is asymptomatic in many cases (1, 2, 4). The incidence of cervicitis is as high as 30-45% in some sexually transmitted infections (STI) among clinic populations (4).
Cervicitis is most often caused by infection (1). Pathogens of Chlamydia trachmatis and Neisseria gonorrhea are the usual culprits (2-4). Less commonly, Mycoplasma genitalium, Mycoplasma hominies, Ureaplasma urealyticum,Trichomona vaginalis,and Herpes simplex Virus are implicated (2,4). The causes of the rest of the cases remain unknown (3,4,7). However, in a few cases it may be attributed to chemical exposure or a foreign body such as a pessary (a device inserted into the vagina to support the uterus), cervical cap (a birth control device), or diaphragm. The condition may also be caused by an allergy to contraceptive spermicides or to latex in condoms (1).
The initial therapy for cervicitis in conventional system is the use of antibiotics and antifungal therapies either orally and topically (4) leading to an imbalance in gut flora due to prolonged use of antibiotics (8). As a side effect, the increased drug resistance has reduced the therapeutic efficacy (4,8,9).
The failure of medical treatment (after two or three attempts) needs further surgical interventions by diathermy, cauterization, cryotherapy, and laser ablation which may cause further complications. None of these treatments not only provides a definite efficacy in spite of their relatively high cost, but also can lead to various adverse events. Due to the nature of these wide-ranging adverse effects, it is important to find effective therapies for genital infections which can be safer, more effective, easily available, and minimal adverse effects.
Complementary and Alternative Medicine (CAM) is progressively accepted and has been interested by the western mainstream medical community because of its less invasive, safer, effective, economical, and convenient therapies. The popularity of CAM has gradually increased, over the last few decades (8). Persian medicine (Iranian traditional medicine (ITM)) with thousands of years of history and hundreds of ancient texts is one of the oldest and richest alternative medicines. Based on ITM literature, cervicitis is known as ″Qoruh-e-Rahem″, and characterized by pain and mucopurulent or bloody discharge. Qoruh is plural of Qarhah (Qorhah) which means wound in muscle tissue of the uterus and cervix. It can be developed by external causes such as bumps and falls (Sagtah) or internal causes such as dystocia, and flow of caustic humor (Insibab Khilt Hadd-e-Marari) to the uterus (10-14).
From ITM perspective, the treatment of cervicitis is a package of interventions, including lifestyle modification, medicinal plant therapies with different pharmacological therapeutic effects, and nondrug techniques such as massage (Dalk) and reflex therapy (Ghamz) used individually or in combination with each other.
The aim of the present study was to review the medicinal plants claimed to be effective on cervicitis based on the Iranian traditional medicine manuscripts that may be used as complementary and/or alternative to conventional treatments, based on the classical medicine, to find out more effective and safer treatment strategies.

Experimental
This study is investigated medicinal plants which were used for the treatment of cervicitis/ Qoruhe-e-Rahem with keywords of Qoruhe-Rahem or Qarhah (Qorhah) in the Iranian Traditional Medicine literature. The herbs were searched and extracted from 7 main traditional medicine reference books including Liber Continent (Al-Havi ) of Rhazes (Abubakr To find matches for old names in modern scientific classification, two botany references (16,(18)(19)(20)(21) and electronic databases as well as the plantlist.org suggested by the research team were used. Moreover, the opinions of distinguished scholars of ITM were also taken into consideration (Table 1).
To investigate the pharmacological properties of the medicinal plants, electronic databases including Pub Med, Scopus, Google Scholar, and Sciencedirect were explored for each of these herbs. All retrieved articles which demonstrate the direct efficacy of these medicinal herbs or their mechanisms involved in cervicitis alleviation including anti-inflammatory, antioxidant, antimicrobial, antibacterial, antifungal, wound healing and analgesic effects were carefully considered in this study. Bibliography in the electronic databases covered all articles published between carefully considered in this study. Bibliography in the electronic databases covered all articles published between years 2000 to 2016. The search terms were ''cervicitis '', ''cervicitis, uterine'', ''uterine cervicitis'', ''cervicitides'', ''cervicitides, uterine'' and ''uterine cervicitides'' in title and abstract as well as the name of each herb in the whole text ( Figure 1).   years 2000 to 2016. The search terms were ''cervicitis'', ''cervicitis, uterine'', ''uterine cervicitis'', ''cervicitides'', ''cervicitides, uterine'' and ''uterine cervicitides'' in title and abstract as well as the name of each herb in the whole text ( Figure 1).

Results and Discussion
After searching for plants effective against cervicitis (Qorohe-Rahem) in the 7 main Iranian Traditional Medicine texts, we reached 31 plants from 21 different families. Table 1, displays the medicinal plants used for the management of cervicitis in Iranian Traditional Medicine and all evidence confirming their efficacy are described individually in Table 2, 3 and 4.
The medicinal plants were categorized into 2 groups; 1) Mofradat which included simple ingredient herbal medicine, 2) Qarabadin which included multi component ingredient herbal medicines (containing 2 or more bioactive pharmaceutical substances) (10, 11, 22). Some routes of administrations for ITM drugs namely oral and topical included intravaginal administration (vaginal suppositories (Ferzajeh/ farzaje, Sheiaf, Homoul, Zarour/Zarur), vaginal lavage/enema (Hoghneh)), external therapy (lotion (Tela), balm (Marham), cleansing (Estenja), steaming washing therapy and sitz bath (Abzan)) and rectal administration (retention enema and rectal infusion with liquid herbal medicine) (8, 22), Ferzajeh and Homoul are two kinds of vaginal suppositories made of components that are kneaded and get dried in shade. Abzan is a traditional remedial sitz bath that is effective in treating gynecology disorders. In this procedure, the patient should sit in a tub filled with water in which a special plant is boiled before. Tela is a kind of lotion used topically. It is used on lower abdominal surface on uterine, pubic, external genitalia, and lumbosacral regions. The other form of drug administration is balm, which is used topically and is named Zemad in Iranian Traditional Medicine, containing some components and suitable liquid part, which makes it pasty. It needs to be dressed with a soft cloth. Cleansing with watery topical preparations is named Estenja (14, 22). Table 2. Studies on anti-inflammatory activities of plants used for treatment of cervicitis cited in ITM references.

Aristolochia longa Aristolochia rotunda
Aqueous extract of root, Hexane and benzene extract of dried root Flavonoides,Saponins/ Aristolochic acid and aristolactam Antifungal, Antibacterial

Myrtus communis
Leaves and fruits from Myrtus communis have been claimed to be effective for the management of cervicitis in different references of ITM. Analgesic (24), Antimicrobial (antibacterial, antifungal and antiviral) and antioxidant properties of compounds produced by M. communis have been reported in numerous studies. 1,8-cineole, linalool, eugenol, terpineol and terpinene as myrtle essential oils components have a good antibacterial effects against some gram positive and gram negative bacteria (25).
As demonstrated in several studies, the antioxidant capacity of plant extracts is strongly related to phenolic content.
This activity is not a property of a single phenolic compound, but it is widely attributed to different phenolic phytochemical constituents. Particularly, anthocyanins, flavonoids and phenolic acids seem to be responsible for the antioxidant capacity of Myrtus communis (25). Rossi et al. in their study revealed that M. communis exerts potent anti-inflammatory effects in-vivo and offers a novel therapeutic approach for the management of acute inflammation (26).
The effects of the essential oil and methanolic extract of Myrtus communis on Trichomonas vaginalis have been shown in Abdollahy et al. study (27).

Peucedanum officinale
Many phytochemical investigations on this genus have confirmed Peucedanum species are rich in essential oils and coumarins. Our review confirmed that some Peucedanum species could have therapeutic effects of anti-inflammatory (30), antioxidant, and antimicrobial (31) .
Commiphora opobalsamum C. opobalsamum is a small tree (5 m in height) that is found in abundance and widespread on mountains around the holy places such as Makkah Al-Mukarama, Al-Madina Al-Munawara (Al-hijaz area, KSA), and Al-Quds (Palestine). In addition, it is native to other areas such as Oman, Yemen, and Somaliland. Anti-inflammatory, antioxidant, and analgesic effects of C. opobalsamum 3.

Commiphora myrha
Ethanol and ether extracts ----  widely distributed in Asia and Europe. The pharmacological evaluation of methanolic extract of the seeds of H. niger showed that it possesses potent analgesic and anti-inflammatory activities. The major chemical components, e.g. coumarinolignans specifically cleomiscosin, which is present in the seeds of H. niger is involved in the anti-inflammatory activity of methanolic extract of the seeds (33).

Artemisia vulgaris
Antimicrobial, antioxidant, and antiinflammatory effects of this plant have been reported in the previous studies (34-36).

Polyporus officinalis Laricifomes officinalis (Polyporus officinalis)
is a wood-rotting fungus that grows on different hosts such as conifers. The mushroom is native to Europe, Asia, and North America. It has been used since the ancient times to treat sciatica, weakness of muscles, bronchitis, constipation, stomach and uterus pain, jaundice, fever, and insect bites. It also has diuretic and emmenagogue effects. The biological effects of L. officinalis including anti-viral (especially against smallpox, H5N1 influenza, and hepatitis C virus), antituberculosis, anticoagulant immunomodulatory, and relieving dysmenorrhea, hemorrhoids, cough, and rheumatoid arthritis were confirmed for this fungus by studies performed in the recent decades (37).

Lowsonia inermis
Inhibitory action of henna against both gram negative and gram positive bacteria was proven (38). Chemical components of L. inermis have good antioxidant capacities and this species could be used as a potential source of new natural antioxidants (39).

Trigonella foenum-graecum
Leaves and seeds from Trigonella foenumgraecum has been claimed to be effective for management of cervicitis in different references of ITM. The anti-inflammatory, antioxidant, antimicrobial, analgesic, and wound healing effects of T. foenum-graecum have been reported (40)(41)(42)(43). The presence of saponins and flavonoids as the major compounds in T. foenum-graecum may explain the anti-inflammatory activity of this plant (44).

Apium graveolens
Anti-inflammatory, antimicrobial and antioxidant effects of A. graveolens have been reported. Baananou reported essential oil and extracts of A. graveolens aerial parts have antiulcerogenic and antibacterial activities (46-48).

Malva sylvestris
In animal models, M. sylvestris presented antinociceptive effects and anti-inflammatory action (49, 50) in mucous membranes and in carrageenan-induced paw edema when applied topically. The antioxidant and radical scavenger properties of this herb (in-vitro) were presented by a study of Della Greca et al. M. sylvestris is effective as an anti-inflammatory agent when used locally in the skin (50). Antimicrobial effects of this plant also have been reported by Gasparetto et al. (49).
One study evaluated the effect of M. sylvestris  topical cream on burn wound healing in the rats. (51).

Allium porrum
Antimicrobial and antioxidant effects of A. porrum were reported by Mnayer et al. (53).

Boswellia carteri
The antimicrobial activity of the essential oil of B. carteri was individually evaluated against different microorganisms including fungi, grampositive, and gram-negative bacteria strains (54). In one study B. carteri was used as a mixture with three plants for diabetic wound healing. The results of this study revealed this treatment is a promising method for wound healing in diabetic mice (55).
Anti-inflammatory, antifungal, antioxidant activities, and analgesic effects of this plant have been reported (56, 57).

Fraxinus excelsior
Antioxidant, antibacterial, and antiinflammatory activities of F. excelsior were shown in the previous reports (58, 59).

Plantago major
The main caffeic acid derivative in P. major is plantamajoside having anti-inflammatory, antioxidant, and antibacterial activities (60). The wound-healing properties of P. major were evaluated using an ex-vivo porcine wound healing model. Ethanol and water extracts stimulated wound healing in porcine skin (61).

Phaseolus vulgaris
Antimicrobial and antioxidant activity of Ph. Vulgaris have been reported (62-64).

Pistacia lentiscus
Resin of P. lentiscus showed 100% inhibition of inflammation at 800 mg/kg i.p. injection, without any toxicity in mice (65). P. lentiscus virgin fatty oil promotes significantly wound contraction and reduces epithelization period in rabbit model (66). Antifungal and antioxidant effects also have been reported (67).

Commiphora myrha
Pharmacological studies showed that myrrh exhibited analgesic, anti-inflammatory, and antimicrobial activities (57, 68). The analgesic activity of Commiphora extract and pure compounds supported the use of myrrh for wound and pain in indigenous medicines (69).
Trachyspermum copticum Trachyspermum copticum, an annual plant which grows in Iran, has white flowers and small fruits. Some biological effects of the fruits of T. copticum such as antiviral, anti-inflammatory, antifungal, analgesic, antinociceptive, and antioxidant activity have been confirmed (70-72).

Narcissus tazetta
Ethanol extracts of aerial parts of this plant showed antimicrobial effects. Aerial parts of N. tazetta have flavonoids, terpenoids, and alkaloids (73, 74).

Verbena Officinalis
Casanova et al. reported 50% methanolic extract and caffeoyl derivatives could be potentially considered as excellent and readily available sources of natural antifungal and antioxidant compounds (75). A topical preparation containing at least 3% of V. officinalis methanolic extract showed an anti-inflammatory and analgesic effects (76).

Foeniculum vulgare
Antioxidant activity of F .vulgare was demonstrated by various studies. The fruits have shown antioxidant activity in animal models. In a study investigating antioxidant properties of different parts of F. vulgare, the shoots had the highest radical scavenging and lipid peroxidation inhibiting activity. Despite of these positive reports, the results of a study on different fractions of fruit and their major chemical compounds did not show strong antioxidant activities from isolated F. vulgare components (77).
Oral administration of a methanol extract of F. vulgare fruits exhibited inhibitory effects against acute and subacute inflammatory diseases and showed a central analgesic activity in rat and mice (77).
F. vulgare essential oil possesses a strong antifungal activity against different fungal species (78) and aqueous extract of F. vulgare has showed potent antibacterial activity (79).

Cydonia oblonga
Quince is a tree cultivated as a medicinal plant in the Middle East, South Africa, and Central Europe. One study indicates that the mucilage obtained from quince seeds accelerates wound healing in rabbits (80). Polyphenolic compounds of C. oblonga were responsible for the antimicrobial effects of this plant (81).
Branca et al. reported the antioxidant activities of quince. Evaluation of the antioxidant activity of methanolic extract of C. oblonga showed that its peel extract has the highest antioxidant capacity. The half maximal inhibitory concentration (IC 50 values) of quince pulp, peel, and jam extracts were correlated with total content of caffeoylquinic acids (82). Essafi-Benkhadir et al. reported anti-inflammatory effect of polyphenolic extract of the C. blonga (83).

Anethum graveolens
Many studies were done about A. graveolens. In these studies antibacterial, antifungal, and antioxidant activity of A. graveolenshas have been confirmed (84-86).

Ficus carica
Antimicrobial, antioxidant and antiinflammatory effects of different dosage forms prepared from different parts/extracts of the F.carica are well documented (87, 88).

Rosa damescena
In Shohayeb et al. study, essential oil and different extracts of petals of the R. damascena were evaluated for their antimicrobial activities against three gram-positive and seven gramnegative bacterias, one acid-fast bacterium and three fungi. Rose oil and all tested rose fractions indicated broad spectrum antibacterial activity against all tested bacteria and fungi (89)

Conclusion
Overall, we found 31 plants from 21 different families cited in the Iranian Traditional Medicine as therapies for cervicitis. Most of these plants had been shown in-vitro and/or in-vivo antiinflammatory, antimicrobial and antioxidant effects (Figure 2). Cervicitis, presenting as inflammation of the uterine cervix, is a syndrome usually caused by infection (113). Oxidative stress, microbial infections, and inflammation are associated with human uterine cervicitis (4, 7, 113). Different mechanisms of action could be considered for these medicinal plants including anti-inflammatory and antimicrobial properties, analgesic, antioxidant activity, and wound healing activities. Finding the medicinal plants effective on cervicitis based on ITM could suggest a better strategy for relieving and management of cervicitis symptoms especially in recurrent or persistent conditions. It should be contemplated that even though exploring ITM literature may lead to the identification of effective natural medicines for the management of different ailments such as cervicitis; however, confirming clinical trials or supportive high-quality observational studies needs to be accomplished before routine administration of herbal medicines or treatment regimens (Tadabeer) recommended in traditional medicine texts to affirm efficacy and safety of these treatments. (1)